Thermodynamic analyses of sickle hemoglobin polymerization provide a model for determining the polymerization potential of hemoglobin mixtures and the sparing effect of fetal hemoglobin and provide insights complementary to kinetic analyses. We have recently shown in solubility assays that under physiological conditions the sparing effects of fetal hemoglobin and hemoglobin A2 are comparable. Calculations based on equilibrium measurements of polymerization of hemoglobin mixtures can predict the extent of sickle hemoglobin polymerization within intact erythrocytes of uniform hemoglobin composition and concentration. These calculations of sickle hemoglobin polymerization have been useful in assessing recent therapeutic strategies for sickle cell anemia based on increasing fetal hemoglobin such as treatment with hydroxyurea or its combination with erythropoietin. Variations in intracellular sickle hemoglobin polymerization tendency, largely due to variations in fetal hemoglobin, numbers of fetal hemoglobin - containing erythrocytes and mean corpuscular hemoglobin concentration in new-born children with sickle cell anemia in the Paris area are being used in a program to predict disease severity and responses to therapy in this well studied group of patients. We are now using these estimates of polymer fraction in studies of the rheological properties of sickle red blood cells using a constructed microrheometer while constantly varying oxygen saturation and measuring rheological changes as a function of polymer fraction and suspending medium for both red cells and hemoglobin solutions. A linear relationship between polymer fraction and viscosity is observed for sickle trait red blood cell suspensions and an exponential relationship between polymer fraction and viscosity for homozygous sickle red blood cell suspensions which becomes more linear below 30% polymer fraction. The microrheometer measured viscosity may be a potential parameter for assessing clinical severity in patients with sickle cell anemia and evaluating the effects of pharmacological agents. For the purpose of creating an animal model for sickle cell disease, we are also producing a transgenic pig using expression constructs for human alpha- and beta-S-globin genes linked to the globin locus control region and the Panepinto miniature swine.